Does the tail wag the dog? How the structure of a glycosylphosphatidylinositol anchor affects prion formation

Abstract

There is increasing interest in the role of the glycosylphosphatidylinositol (GPI) anchor attached to the cellular prion protein (PrPC). Since GPI anchors can alter protein targeting, trafficking and cell signaling, our recent study examined how the structure of the GPI anchor affected prion formation. PrPC containing a GPI anchor from which the sialic acid had been removed (desialylated PrPC) was not converted to PrPSc in prion-infected neuronal cell lines and in scrapie-infected primary cortical neurons. In uninfected neurons desialylated PrPC was associated with greater concentrations of gangliosides and cholesterol than PrPC. In addition, the targeting of desialylated PrPC to lipid rafts showed greater resistance to cholesterol depletion than PrPC. The presence of desialylated PrPC caused the dissociation of cytoplasmic phospholipase A2 (cPLA2) from PrP-containing lipid rafts, reduced the activation of cPLA2 and inhibited PrPSc production. We conclude that the sialic acid moiety of the GPI attached to PrPC modifies local membrane microenvironments that are important in PrP-mediated cell signaling and PrPSc formation.